Variations in the copy number of a given gene, also known as copy number variation (CNV) or copy number polymorphisms (CNP), when the frequency exceeds 1%, is a heritable property. CNVs of specific target genes have been associated with complex phenotypes such as cancer and inflammatory bowel disease. Indeed, CNV of the target gene, TLR7, has been associated with the autoimmune phenotype in BXSB mice, and recent data in the human Fc receptor locus suggest that CNV of a neutrophil specific gene in this region may also be important in autoimmune diseases. We now have data that demonstrate that there are multiple types of structural variation in the Fc receptor region, both deletions of varying extents and duplications. Furthermore, since the genes immediately adjacent FCGR3B are pathophysiologically important, we hypothesize that the full repertoire of activating and inhibitory FcR genes involved in these structural variations may be most important. In particular, FCGR2C, thought by most to be a pseudogene, encodes a protein expressed on B cells and provides a counterbalancing signal to the classical concept of the FCGR2B-mediated brake on immune complex driven B cell activity. We hypothesize that the nature and frequency of these CNVs will be distinct in African Americans, and perhaps Hispanics, compared to Caucasians and that these differences will contribute to the severity of the disease phenotype over time in both of these groups. In this Program Project, we have the unique opportunity to define the structural variations of this genetically and pathophysiologically important region, in ethnic minorities, and to relate this variation to both disease susceptibility and disease severity over time. Our Specific Aims are 1) To define the nature of copy number variation in the classical Fc receptor cluster and its relationship to SLE, 2) To define the relationship between ancestry and the types of copy number variants and 3) To examine other genes in the opsonin / immune complex pathway for copy number variation and relate this variation to overall SLE risk. Relationship of Project with Overall PPG Priorities. The proposed research plan will examine the importance of CNV in Fc receptors and other pathway genes. The project will also look at interactions between genetic ancestry markers and CNV for SLE susceptibility and severity. This research plan will (1) work with Projects 2 and 3 to identify regional AIMs, (2) draw on the expertise of the Genetic Epidemiology and Biostatistics Cores in the design and analysis of CNV in relation to regional AIMs, increase collaboration between partner institutions, (3) foster the continued development of an effective Rheumatic Diseases Research Program, (4) enhance research efforts toward SLE-related health disparities and (5) provide novel insight to the genetic etiology of SLE as an autoimmune phenotype that is disproportionately more frequent and severe among ethnic minority populations.